The use of filled gelatin capsules as delivery devices is well-known in many art fields, especially the pharmaceutical sciences. In pharmaceutical applications, filled gelatin capsules are especially suitable as a means to orally administer a pharmaceutical product to a subject.
It is known that the presence of certain ingredients in the filling promote crosslinking in the gelatin shell with the passage of time and/or under stress conditions. When crosslinking occurs, the gelatin shell becomes less soluble in aqueous media, especially acidic aqueous media. Crosslinking causes retardation of the disintegration of the capsule shell, and thus retardation of the dissolution of the capsule contents, relative to identical capsules which have not been subjected to the passage of time or stress conditions. Thus, when a filled gelatin capsule contains an ingredient which promotes crosslinking in the gelatin shell, it is a challenge to prepare a formulation which does not show retarded disintegration and/or dissolution when the filled capsule is subjected to the passage of time and/or stress conditions.
It is likely that crosslinking has a much greater impact on the results of in vitro dissolution testing than on the in vivo bioavailability of drugs formulated in gelatin capsules. However, since in vitro dissolution testing is commonly employed as a method of measuring the stability of drug products, it is important to utilize a capsule fill which minimizes crosslinking in the capsule shell and thus minimizes the impact of time and/or stress conditions on the dissolution profile of the filled gelatin capsule, especially during accelerated stability studies wherein the capsules are subjected to high temperature and relative humidity.
The present invention relates to the discovery that the effects of crosslinking in a gelatin capsule which contains a material that promotes crosslinking are reduced or eliminated by incorporating an effective crosslinking-reducing amount of a combination of at least one amino acid and at least one carboxylic acid in the capsule fill. Both the amino acid and the carboxylic acid are required to obtain the beneficial effects of the present invention.